Longevity Papers

Aging is associated with increases in risk of multiple chronic diseases and at the cellular level, with disruptions in RNA homeostasis. Single-cell transcriptomic studies have revealed RNA abundance heterogeneity across brain cell types but the more complex changes in RNA processing such as alternative splicing, isoform usage, transcription start and polyadenylation site selection remain uncharacterized. Here, we combine single-cell analysis with long-read nanopore sequencing to capture full-length RNA isoforms and uncover temporal changes in RNA transcription, processing, and alternative splicing in the aging mouse cortex and hippocampus. By profiling transcriptomes from young adult to very old mice, we identify non-linear, cell-type-specific isoform expression changes and isoform usage shifts, primarily driven by transcription start site selection. These aging-associated isoform changes alter the coding potential and poly(A) site position of genes. Our data also reveal a high proportion of senescence in immune cells, far exceeding that of other cell types. We also identify isoform markers that, when applied to a machine learning model, distinguish senescent from normal immune cells. This study provides a full-length RNA isoform-based atlas of the aging mouse brain, offering insights into RNA metabolism remodeling across brain cell types throughout the lifespan.

Adipose tissue plasticity and functional heterogeneity play a central role in maintaining energy homeostasis, and their malfunction leads to metabolic disorders such as obesity, diabetes, and cardiometabolic disease. Rapid, single-cell metabolic imaging of intact fat tissue not only extends our understanding of metabolic dynamics and heterogeneity but also holds great potential as a tool for clinical diagnosis. However, the use of exogenous labels and dyes in conventional optical microscopy results in tissue deformation and requires time-consuming tissue preparation. Here, we demonstrated single-cell imaging of metabolic changes and heterogeneity in freshly excised adipose tissues that can distinguish tissue types without the need for exogenous labels using bond-specific, non-destructive, mid-infrared optoacoustic microscopy (MiROM) that allows preserving the native tissue architecture with minimal sample preparation time. Further leveraging MiROM, we monitored intracellular molecular and morphological changes during postnatal remodeling of adipose tissue when metabolic characteristics of adipocytes undergo a transient drastic change. Additionally, we developed an AI-based quantitative spatial tissue analysis tool (Q-SAT) to predict the spatial distribution of white fat- and brown fat-like features, providing a robust digital scoring method for adipose tissue phenotypic assessment. Collectively, we implemented MiROM as an enabling technology to provide fast, label-free metabolic imaging of unprocessed adipose tissue, opening a new perspective for understanding and characterizing the morpho-functional dynamics of adipose tissue remodeling.

Cellular senescence (CS) is a hallmark of ageing and age-related diseases. While dietary interventions are often explored to reduce CS, less is known about dietary ingredients that induce it. This study systematically reviews the evidence on dietary ingredients that promote CS in animal models and humans.

Age and sex exert profound influences on the heart, shaping its structure, function, and susceptibility to disease. Among the myriad of changes driven by age and sex, alterations in the extracellular matrix (ECM), particularly collagen influence myocardial health in aging. Collagen, the predominant ECM protein, upholds tissue integrity and function through tightly regulated processes. Aging, a significant cardiovascular risk factor, is linked to increased collagen deposition, left ventricular remodelling, and fibrosis. Similarly, sex differences affect cardiovascular disease progression, with notable variations in the deposition of collagen types I and III between males and females. While collagen accumulation is present in aging in both sexes, females exhibit a tempered response until menopause, primarily due to oestrogen-mediated suppression of excessive collagen remodelling. This review focuses on the mechanisms underlying age- and sex-related changes in cardiac collagen metabolism and their implications for myocardial health. Aging-associated fibrosis and collagen accumulation appear mechanistically distinct from those seen with injury or dysfunction, occurring without increased collagen synthesis despite elevated degradation enzymes. Factors such as senescence, inflammation, oxidative stress, and enhanced ECM crosslinking are identified as key drivers of these metabolic shifts. While studies in ovariectomized rodent models have highlighted the role of sex in collagen metabolism, evidence suggests that aging exerts a more dominant influence overall. Additionally, this review emphasizes a critical gap in the field: the limited availability of longitudinal aging fibrosis studies that include both sexes. This scarcity hampers a comprehensive understanding of how aging and sex collectively shape collagen turnover and myocardial health. By assessing these knowledge gaps, the review aims to define current perspectives and may provide insights to help inform the development of more effective, targeted therapeutic approaches.

Transcranial photobiomodulation (tPBM), as a novel non-invasive neurostimulation technique, has shown the compelling potential for improving cognitive function in aging population. However, the potential mechanism remains unclear. Neuroimaging studies have found that tPBM-induced physiological changes exist in both targeted and non-targeted brain areas, suggesting the necessity of understanding the modulation mechanism from the perspective of the whole brain level.

Kompot is a statistical framework for holistic comparison of multi-condition single-cell datasets, supporting both differential abundance and differential expression. Differential abundance captures changes in how cells populate the phenotypic manifold across conditions, while differential expression identifies condition-specific changes in gene regulation that may be localized to particular regions of that manifold. Kompot models the distribution of cells and gene expression as continuous functions over a low-dimensional representation of cell states, enabling single-cell resolution inference with calibrated uncertainty estimates. Applying Kompot to aging murine bone marrow, we identified a continuum of shifts in hematopoietic stem cell and mature cell states, transcriptional remodeling of monocytes independent of compositional changes, and divergent regulation of oxidative stress response genes across cell types. By capturing both global and cell-state specific effects of perturbation, Kompot reveals how aging reshapes cellular identity and regulatory programs across the hematopoietic landscape. This framework is broadly applicable to dissecting condition-specific effects in complex single-cell landscapes.

Post-translational modifications (PTMs) regulate protein homeostasis, but how aging impacts PTMs remains unclear. Here, we used mass spectrometry to reveal changes in hundreds of protein ubiquitylation, acetylation, and phosphorylation sites in the mouse aging brain. We show that aging has a major impact on protein ubiquitylation. 29% of the quantified ubiquitylation sites were affected independently of protein abundance, indicating altered PTM stoichiometry. Using iPSC-derived neurons, we estimated that 35% of ubiquitylation changes observed in the aged brain can be attributed to reduced proteasome activity. Finally, we tested whether protein ubiquitylation in the brain can be influenced by dietary intervention. We found that one cycle of dietary restriction and re-feeding modifies the brain ubiquitylome, rescuing some but exacerbating other ubiquitylation changes observed in old brains. Our findings reveal an age-dependent ubiquitylation signature modifiable by dietary intervention, providing insights into mechanisms of protein homeostasis impairment and highlighting potential biomarkers of brain aging.

Intermittent fasting (IF) is increasingly recognized as an effective dietary intervention for slowing aging process and alleviating metabolic disturbances in multiple chronic diseases, especially in cardiovascular diseases (CVDs). Despite recent progress, the mechanisms behind its effects on cardiovascular health from the perspective of circadian rhythms are not yet fully understood. This review aims to explore the interaction between IF and circadian rhythms, focusing on their combined effects on cardiometabolic risks and cardiovascular outcomes. Evidence from animal models and clinical trials suggests that IF provides protective effects against cardiac damage and dysfunction. It is also indicated that IF influences key cardiometabolic risk factors, such as insulin sensitivity, inflammation, and lipid metabolism, by aligning with the intrinsic biological rhythms. Additionally, we discuss the therapeutic potential of IF in cardiovascular outcomes, particularly in individuals with circadian disruptions. This review also highlights future research directions to identify the most effective fasting protocols and assess the long-term cardiovascular benefits of IF in disease prevention and treatment.

Pulmonary fibrosis is often associated with aging, marked notably by the senescence of lung epithelial cells and the development of interstitial fibrosis. Mitophagy plays a crucial role in aging by degrading damaged mitochondria, thereby maintaining mitochondrial quality and cellular homeostasis. When mitophagy is disrupted or impaired, damaged mitochondria fail to be properly degraded by lysosomes. This results in the persistence of dysfunctional mitochondria, which can further damage cells, induce cell senescence and trigger inflammatory responses. These processes can worsen pulmonary fibrosis. Restoring proper mitophagy could be a promising strategy for managing pulmonary fibrosis and countering stress-induced premature cell senescence, potentially improving or even reversing lung function in aging lungs. This review will explore the complex relationship between cell senescence and pulmonary fibrosis, detailing the senescence characteristics in fibrotic lungs. It will also highlight recent advancements in understanding how mitophagy influences lung senescence and fibrosis and discuss potential therapeutic strategies to address mitophagy dysfunction in treating pulmonary fibrosis.

Serum Klotho, a biomarker associated with anti-aging, has been implicated in kidney disease. However, there is a lack of robust evidence for the relationship between the serum Klotho and diabetic kidney disease (DKD). This study aimed to investigate the association of the serum Klotho levels with DKD and assess the relationship between serum Klotho and all-cause mortality in individuals with DKD.

While healthy lifestyles mitigate the risk of multimorbidity (≥ 2 chronic diseases), their temporal dynamics in aging populations, particularly in low- and middle-income countries undergoing rapid demographic structure transition, remain understudied.

Aging-related cognitive impairment seriously diminishes individuals' life quality. Icariin (ICA), a natural flavonoid separated from the herb

Aging, a complex physiological process characterized by multi-organ involvement and closely associated with oxidative stress and chronic inflammation, has prompted growing scientific interest in natural antioxidant probiotics due to their dual health-promoting properties and anti-oxidative capabilities. However, the effectiveness and mechanisms of multiple emerging Lacticaseibacillus rhamnosus (L. rhamnosus) strains extracted from the fecal microbiota of breastfed infants on zebrafish models remain unclear. In this study, the anti-aging potential of L. rhamnosus NKU FL1-11, selected for its potent inhibition of senescence-associated β-galactosidase activity, was systematically investigated using H

Osteonecrosis of the femoral head (ONFH) is a disabling orthopedic disease characterized by hyperactivation of osteoclasts and impairment of osteogenesis. However, the underlying mechanism by which osteoclastogenesis is driven in ONFH remains unclear. Although cellular senescence is hypothesized to contribute to the development of multiple comorbidities, the role of cellular senescence in ONFH remains underexplored. In this study, we explored whether clearing senescent cells ameliorates ONFH. Analyses of single-cell sequencing data revealed that the population of osteoclasts increased in ONFH, and the expression of senescence-related genes (CDKN1A and CDKN2A) in macrophages was elevated in ONFH patients. Additionally, we found that senescent macrophages in ONFH mice were significantly increased, as evidenced by an increased population of SA-β-gal positive cells and F4/80

Ageing is a key driver of the major diseases afflicting the modern world. Slowing or reversing the ageing process would therefore drive significant and broad benefits to human health. Previously, the Yamanaka factors (OCT4, SOX2, KLF4, with or without c-MYC: \"OSK(M)\") have been shown to rejuvenate cells based on accurate predictors of age known as epigenetic clocks. Unfortunately, OSK(M) induces dangerous pluripotency pathways, making it unsuitable for therapeutic use. Recent work has focused on minimising the danger of the cocktail, but safety concerns remain. Here we present \"SB000\", the first single gene intervention to rejuvenate cells from multiple germ layers with efficacy rivalling the Yamanaka factors. Cells rejuvenated by SB000 retain their somatic identity, without evidence of pluripotency or loss of function. These results reveal that decoupling pluripotency from cell rejuvenation does not remove the ability to rejuvenate multiple cell types. This discovery paves the way for cell rejuvenation therapeutics that can be broadly applied across age-driven diseases.

Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian lifespan and protects against a range of age-related diseases. Surprisingly though, we found that reduced IGF-1 signaling fails to extend the lifespan of mitochondrial mutator mice. Accordingly, most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the pro-longevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome and that mitochondrial mutations may impose a hard limit on mammalian lifespan. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.

Older adults are susceptible to infections, in part due to waning of immune memory. To determine mechanisms that determine long-lasting versus short-term immunity, we examined varicella zoster virus (VZV) vaccination as a model system. We contrasted VZV antigen-specific T cells several years after vaccination in adults who had been vaccinated at young (<20 years) or older age (>50 years) with a live-attenuated vaccine that confers durable protection only when given at young age, or with an adjuvanted VZV component vaccine that elicits effective, long-lasting immunity in older adults. CD8+ T cells were highly sensitive to age-related changes showing T cell subset shifts, loss in TCR diversity and reduced stem-like features while gaining NK-like signatures without evidence for cellular senescence or exhaustion. VZV-specific CD4+ T cells were largely resilient to age and maintained phenotypic and TCR diversity. Immunization of older adults with the adjuvanted VZV vaccine did not reverse age-associated defects in CD8+ T cells. Instead, it selectively improved the functionality of VZV-specific Th17 CD4+ T cells and prevented their acquisition of Treg features, likely as consequence of lipid metabolic pathways. Collectively, our data indicate that effective vaccination in older adults is supported by the generation of a durable, antigen-specific CD4+ Th17 population that resists mis-differentiation into Tregs and that compensates for age-related defects in CD8+ T cells.

Advanced glycation end products (AGEs) are a heterogeneous group of compounds formed during the advanced stages of the Maillard reaction through non-enzymatic reactions, occurring mainly between reducing sugars or their oxidation metabolites and amino groups in proteins, lipids, and nucleic acids. These compounds can be endogenously formed, particularly under hyperglycemic conditions. In addition, AGEs are also produced exogenously during the thermal processing of foods, contributing to the dietary intake of these compounds. The accumulation of AGEs in body tissues has been associated with aging and the pathogenesis of various non-communicable diseases. Dietary intake of AGEs contributes significantly to their systemic burden. Consequently, reducing the intake of dietary AGEs has been proposed as a modifiable risk factor for the prevention of chronic, age-related diseases. This review examines and discusses current evidence on the molecular mechanisms by which dietary and endogenous AGEs contribute to cellular senescence and the progression of prevalent age-associated pathologies, including diabetes, cardiovascular diseases, musculoskeletal disorders, and neurodegeneration.

The food system is a key determinant of population and planetary health. As the "one planet, one health" approach gains momentum, evaluating "food biodiversity" and its association with mortality in high-risks populations is increasingly important. Hence, we evaluated the associations of food biodiversity with all-cause and cause-specific mortality in a Spanish cohort of older adults at high cardiovascular risks. Food biodiversity was defined using dietary species richness (DSR), the count of unique plants and animal species consumed by an individual. DSR was cumulatively calculated over the PREDIMED study follow-up, using yearly food frequency questionnaire data. The association of food biodiversity with all-cause and cause-specific mortality was assessed using Cox regression, while controlling for confounders. We analyzed data from 7210 participants (58 % women), with a median age of 67 years. DSR in the cohort ranged between 16 and 57 (median: 48). Over a median follow-up of 6 years, 425 deaths were recorded (103 deaths from cardiovascular diseases (CVD), 169 cancer deaths, and 153 deaths due to other-causes). DSR was only moderately correlated with adherence to the Mediterranean diet. On average, when fully adjusted, every additional species over the follow-up period was associated with a Hazard Ratio (HR (95 % Confidence Interval) of 0.91(0.90,0.93) for all-cause mortality, 0.93(0.90,0.96) for CVD mortality, 0.92 (0.89,0.94) for cancer deaths, and a 0.91(0.89,0.94) for deaths from other causes. Dietary recommendations to improve food biodiversity may increase longevity.

Loss of Y chromosome (LOY) and clonal hematopoiesis of indeterminate potential (CHIP) are common age-related events associated with multiple adverse outcomes in the elderly. While LOY has been associated with higher risk of Alzheimer disease (AD), CHIP has been suggested to perform a protective role against AD. Moreover, the co-occurrence of CHIP and LOY is debated. We performed deep whole-exome sequencing of FACS-isolated CD4T lymphocytes, NK and myeloid cells from men with AD and controls exhibiting either LOY or retention of Y chromosome (ROY). We found 39 sequence variants in known (canonical) myeloid driver genes of clonal hematopoiesis (MD-CH) and known lymphoid driver genes (LD-CH), and maximally 14(35%) of these could co-exist with LOY within the same clone. We further describe 192 unknown drivers of clonal hematopoiesis (UD-CH), which were markedly enriched in AD-LOY individuals (odds ratio=4.8, Benjamini-Hochberg adjustedp=0.041), and over 20% of these variants were protein-truncating. In myeloid cells, the total burden of all detected drivers correlated with the percentage of LOY cells (Spearman{rho}=0.52, adjustedp=0.00041). In conclusion, our findings suggest that LOY acts as the primary driver of clonal hematopoiesis in AD by seeding myeloid clones. These clones may subsequently accumulate additional, often truncating, UD variants, while most canonical CHIP mutations arise independently of LOY. Our study delineates distinct yet partially overlapping clonal architectures for LOY and CHIP in late-onset AD and underscores LOY-driven myeloid expansion as a potential contributor to disease pathogenesis.

Background: Although the connection between aging and neurodegenerative pathologies like Alzheimer\'s disease (AD) has long been recognized, the underlying pathological mechanisms remain largely unknown. Senescent brain cells build up in the brains of AD patients and a causal link has been established between senescence and AD-related tauopathy. Methods: To investigate the role of cellular senescence in tau-mediated neuropathology, we crossed the Terc knockout (Terc-/-) senescent mouse model with the P301S tauopathy model (PS19 line). Using brain sections and protein extracts, we employed Western blot and immunostaining analyses to investigate the expression of tau-related neuropathological features within a senescent context. Results: We found that the brains of 6- and 9-month-old Terc-/- mice exhibit significant telomere attrition and signs of cellular senescence. Introducing a senescent phenotype in a tauopathy mouse model resulted in increased tau phosphorylation at key residues, particularly in the hippocampus. Over time, this was associated with enhanced tau truncation and aggregation. These pathological changes were accompanied by exacerbated astrocyte and microglial activation, as well as selective neuronal loss in vulnerable brain regions. Conclusions: Overall, our findings place senescence as a key upstream regulator of tau pathology, suggesting that targeting senescent cells and their detrimental effects may offer promising therapeutic strategies for AD and other related tauopathies.

Gait alterations are recognized as early markers of age-related decline and cognitive impairment. Dual-task assessments, which impose cognitive load while walking, provide valuable insights into gait control limitations and cognitive-motor interactions in aging populations. This study evaluates age-related and cognitive load-induced changes in gait parameters, with a particular focus on asymmetry, and aims to optimize the gait assessment protocol for the Semmelweis Study framework. The Semmelweis Study is a large-scale workplace cohort investigating the determinants of unhealthy aging and promoting healthy brain aging by identifying risk factors and protective mechanisms influencing vascular, metabolic, and neurocognitive decline. As part of this initiative, gait analysis is emerging as a critical tool for assessing functional aging, detecting early signs of mobility and cognitive impairment, and contributing to biological age assessment. A cross-sectional analysis was conducted on adults aged 23 to 87 years using a pressure-sensitive walkway system. Participants were evaluated under single-task conditions (normal walking) and dual-task conditions (walking while performing a concurrent cognitive task). Spatiotemporal gait parameters, asymmetry indices, and dual-task costs were analyzed to assess age-related changes in gait performance and cognitive-motor interactions. Aging was associated with significant reductions in gait speed, step length, and stride length, along with a corresponding increase in gait asymmetry. Dual-task conditions exacerbated these alterations, indicating age-related impairments in cognitive-motor integration. Asymmetry indices were sensitive to aging effects, suggesting their potential as biomarkers for functional decline. The dual-task cost on gait was significantly greater in older adults, reinforcing the interplay between cognitive and motor systems in aging. Age-related gait alterations, particularly under cognitive load, underscore the importance of comprehensive gait assessments in aging research. Our findings contribute to the optimization of the Semmelweis Study gait assessment protocol by identifying key gait parameters that capture functional decline and biological aging. Integrating dual-task gait analysis into large-scale epidemiological studies has the potential to enhance early detection of brain health decline, refine biological age estimation, and guide targeted interventions to support healthy aging and neuromotor resilience.

Ultraviolet radiation is a major factor in causing skin aging. Compared to younger individuals, older adults exhibit a significant imbalance in the M1/M2 macrophage ratio, with an elevated proportion of M1 macrophages, but little is known about the role of macrophages in skin aging. Here, we report the critical role of M2 macrophages and PKM2 in preventing fibroblast photoaging. UVB-treated photoaged fibroblasts showed a reduction in PKM2. Compared to M1 macrophages, treatment with M2 macrophage significantly alleviated this photoaging and enhanced PKM2 synthesis in fibroblasts. Mechanistically, this is due to the secretion of CCL1 by M2 macrophages, which acts on the CCR8 receptor on the cell surface, promoting PKM2 production in photoaged fibroblasts. This further activates the TGF-β1/Smad2 pathway, thereby reducing cellular aging. This provides a potential strategy for the treatment of skin photoaging.

Identifying factors that contribute to the age-related onset of chronic obstructive pulmonary disease (COPD) is crucial for its prevention and treatment. The multifunctional endoplasmic reticulum (ER) chaperone protein disulfide isomerase A1 (PDIA1) shows a protective increase in expression levels in human and mouse non-COPD smokers. However, this increase slows with aging and disease progression, while increase in glutathione S-transferase π1 (GSTP1) does not. PDI has redox sensitive cysteine residues that can become S-glutathionylated (PDI-SSG) which compromise both isomerase and chaperone activity. Oxidized PDIA1 levels progressively rise with age in the lungs of murine non-smokers, with an even greater increase in smokers. To investigate whether an increased oxidized-to-native PDIA1 ratio (PDI-SSG/PDI-SH) contributes to the depletion of alveolar epithelial type 2 progenitor cells in COPD, we used the type-2-like cell line MLE12. High doses of cigarette smoke (CS) induced elevated oxidized PDIA1 levels, while a redox-refractory PDIA1 variant maintained a lower PDI-SSG/PDI-SH. Upon CS exposure, PDIA1 was S-glutathionylated by GSTP1 and predominantly localized at the ER-mitochondria interface. This mitochondrial proximity was prevented by pharmacological or genetic GSTP1 inhibition. When localized at the ER-mitochondria interface, S-glutathionylated PDIA1 decreased mitochondrial membrane potential (MMP), facilitated mitochondrial permeability transition pore opening, decreased mitochondrial respiration and triggered cytochrome c (Cyt c) release, followed by caspase-3 activation. Isolated mitochondrial studies confirmed that PDI-SSG trigger these apoptotic signals whereas native PDI does not. Our findings indicate that GSTP1-mediated S-glutathionylation of PDIA1 drives pro-apoptotic intraorganellar signaling by altering its ER distribution. Overexpression of a redox-refractory PDIA1 variant restored MMP and reduced Cyt c release, suggesting that a lower S-glutathionylated-to-native PDIA1 ratio is protective. These findings highlight a threshold-dependent regulation of PDIA1-SSG/PDIA1-SH redox signaling. We propose that the simultaneous inability to maintain high PDIA1 levels and the age-associated increase in its S-glutathionylated form in smokers accelerates AEC2 depletion and exhaustion, thereby contributing to emphysema progression.

Age-related decline in intrinsic capacity (IC), defined as the sum of an individual's physical and mental capacities, is a cornerstone for promoting healthy aging by prioritizing maintenance of function over disease treatment. However, assessing IC is resource-intensive, and the molecular and cellular bases of its decline are poorly understood. Here we used the INSPIRE-T cohort (1,014 individuals aged 20-102 years) to construct the IC clock, a DNA methylation-based predictor of IC, trained on the clinical evaluation of cognition, locomotion, psychological well-being, sensory abilities and vitality. In the Framingham Heart Study, DNA methylation IC outperforms first-generation and second-generation epigenetic clocks in predicting all-cause mortality, and it is strongly associated with changes in molecular and cellular immune and inflammatory biomarkers, functional and clinical endpoints, health risk factors and lifestyle choices. These findings establish the IC clock as a validated tool bridging molecular readouts of aging and clinical assessments of IC.

Hematopoietic mosaic Loss Of Y chromosome (LOY), a condition referring to the age-related loss of Y chromosome in a subset of blood cells, is associated with shortened life expectancy and increased risk of age-related diseases in men. Despite Valvular Heart Disease (VHD) becoming more prevalent with aging, the underlying risk factors and mechanisms leading to sex-related differences in VHD remain unclear.

Intervertebral disc degeneration (IVDD) is a common pathology involving various degenerative diseases of the spine, with nucleus pulposus cell (NPC) senescence playing an important role in its pathogenesis. Transcriptional and epigenetic processes have been increasingly implicated in aging and longevity. E74-like factor 1 (ELF1) is a member of the erythroblast transformation specific family of proteins, which induce gene transcription by binding to gene promoters or enhancer sequences. However, the role of ELF1 in age-related diseases is unclear, with no reports of its involvement in NPC senescence or IVDD. ELF1 expression levels were assessed in human NP samples from IVDD patients, IVDD animal models, and naturally aged NP samples. Adeno-associated virus 5 (AAV5) vector-mediated Elf1 overexpressing mice and Elf1 knockout (KO) mice were used to investigate its role in NPC senescence and IVDD in vivo. The m6A methylase METTL3 and reading protein YTHDF2 were identified as downstream effectors of ELF1 using proteomic sequencing, RNA sequencing, ChIP-seq, promoter prediction, and binding analyses. MepRIP-qPCR, RNA pulldown, and double luciferase point mutation experiments revealed that METTL3 and YTHDF2 can recognize the m6A site on E2F3 mRNA, a key cell cycle gene. Finally, virtual screening techniques and various experiments were used to identify small molecule targets for ELF1 inhibition. ELF1 was found to drive m6A modification changes during NPC aging. The small molecule mycophenolate mofetil (MMF) could successfully target and inhibit ELF1 expression. In senescent NPCs, ELF1 can bind to the METTL3 and YTHDF2 gene promoter regions. Overexpressing METTL3 increased the E2F3 mRNA m6A modification abundance, while YTHDF2 was recruited to recognize this m6A site. This can accelerate the E2F3 mRNA degradation rate and ultimately lead to the onset of G1/S cell cycle arrest in NPC. For the first time, the transcription factor ELF1 has been identified as a novel regulator of NPC senescence and IVDD, which involves the ELF1-METTL3/YTHDF2-m6A-E2F3 axis. MMF, a small molecule designed to inhibit ELF1 and delay NPC senescence, was screened for the first time. This can potentially lead to new epigenetic therapeutic strategies for drug discovery and development for the clinical treatment of IVDD.

Metformin, traditionally promoted for its efficacy in diabetes, is increasingly appreciated for its geroprotective potential in the development of vascular aging, a key contributor to cardiovascular morbidity. This review aims at understanding the spectrum of mechanisms that govern the amelioration of degenerative processes associated with vascular aging by metformin. Central to this therapeutic promise is the activation of AMPK, which reduces metabolic dysregulation and hence slows vascular senescence. Oxidative stress has been identified as an important mechanism thought to be enhanced by metformin in the preservation of endothelial function and attenuation of arterial stiffening. Besides, metformin has lipid-lowering and antiinflammatory activity, which is critical for reducing arterial rigidity and the development of atherosclerotic plaque. In recent times, both clinical and preclinical studies revealed empirical data that confirmed the effectiveness of metformin in the improvement of endothelial function and the decreasing of arterial stiffness as a part of a reduction in the rates of cardiovascular events. The therapeutic action of the drug goes beyond glycemic control, rendering it a geroprotector potentially suitable for broader application in age-related vascular decline. In light of these findings, the clinical acceptance of metformin as an intervention in vascular aging should be possible and promising. Carefully monitored follow-up studies are needed to optimize dosing, delineate the broad biological effects, and verify long-term benefits, which will underpin metformin's role in the paradigm against age-associated vascular diseases.

Benign prostatic hyperplasia (BPH) is a common age-associated urological condition characterized by stromal expansion, but its cellular origins and regulatory mechanisms remain unclear. In this study, we identified endothelial-to-mesenchymal transition (EndMT) as a contributor to stromal cell accumulation in BPH. Using single-cell transcriptomic analysis, endothelial lineage tracing in mice, and validation in human samples, we showed that senescence-associated mast cells increased the expression of vascular endothelial growth factor A (VEGFA) and transforming growth factor-beta 1 (TGF-{beta}1) through the stem cell factor (SCF)/c-KIT-MAPK-JUND signaling pathway, thereby inducing EndMT in endothelial progenitor cells. Stromal fibroblasts express SCF, promoting mast cell activation and establishing a feedback loop that supports continued stromal proliferation. Intriguingly, inhibition of mast cell activation reduces EndMT and attenuates prostate enlargement in vivo.Thus, these findings revealed a senescence-linked immune - stromal interaction in the aging prostate and identify potential targets for therapeutic intervention in BPH.

This study aimed to explore the relationships between lipid metabolism indices-the Lipid Accumulation Product (LAP), Visceral Adiposity Index (VAI), Cardiac Metabolic Index (CMI), and Atherogenic Index of Plasma (AIP)-and sarcopenia in individuals aged ≥ 60 years, and to investigate the mediating role of uric acid (UA) in these relationships. The goal was to provide scientific evidence and practical guidance for preventing and treating sarcopenia in older adults.

Intrinsic Capacity (IC) is a crucial measure of the comprehensive physiological and psychological capabilities of older adults, playing a key role in assessing healthy aging. This systematic review aims to explore the trajectories of IC in older adults, as well as the associated determinants and health outcomes. By searching through PubMed, Embase, Ovid, and Web of Science databases, we identified 13 studies that met our inclusion criteria. To ensure the rigor of the review, the Newcastle-Ottawa Scale (NOS) critical appraisal tool for cohort studies and the Guidelines for Reporting on Latent Trajectory Studies were employed to assess the quality of the studies included. When IC is represented as a single composite value, there are primarily three trajectory types: declining trajectory (characterized by a sharp, moderate, or mild decline from baseline IC), stable trajectory (little change compared to baseline IC), and high trajectory (high baseline IC with an increasing trend). When IC is broken down into individual dimensions, these trajectories primarily reflect the degree of impairment in different domains and changes in IC status. The trajectories can be divided into robust status (no impaired domains, stable IC status), mild impairment (impairment in 1-2 domains, mild IC impairment), and severe impairment (impairment in multiple domains, severe IC impairment). Factors influencing IC trajectories include age, gender, education level, ethnicity, number of chronic diseases, marital status, perceived financial adequacy, economic assistance status, self-assessed health status, and inflammatory biomarkers (such as IL-6, TNFR-1, and GDF-15). Adverse IC trajectory patterns are associated with increased mortality, quality of life, disability, frailty, and fall risk. Future research should focus on changes in IC at the end of life, increase the number of assessment time points, use objective measurement methods, and consider experimental designs to better understand the mechanisms behind IC trajectories, providing a scientific basis for targeted interventions.

As the prevalence of age-related diseases rises, understanding and modulating the aging process is becoming a priority. Transcriptomic aging clocks (TACs) hold great promise for this endeavor, yet most are hampered by platform or tissue specificity and limited accessibility. Here, we introduce Pasta, a robust and broadly applicable TAC based on a novel age-shift learning strategy. Pasta accurately predicts relative age from bulk, single-cell, and microarray data, capturing senescent and stem-like cellular states through signatures enriched in p53 and DNA damage response pathways. Its predictions correlate with tumor grade and patient survival, underscoring clinical relevance. Applied to the CMAP L1000 dataset, Pasta identified known and novel age-modulatory compounds and genetic perturbations, and highlighted mitochondrial translation and mRNA splicing as key determinants of the cellular propensity for aging and rejuvenation, respectively. Supporting Pasta\'s predictive power, we validated pralatrexate as a potent senescence inducer and piperlongumine as a rejuvenating agent. Strikingly, chemotherapy drugs were highly enriched among pro-aging hits. Taken together, Pasta represents a powerful and generalizable tool for aging research and therapeutic discovery, distributed as an easy-to-use R package on GitHub.

Debate regarding the premature aging of knee joints in acquired immune deficiency syndrome (AIDS) patients has remained contentious, with conjectures pointing towards its correlation with distinct antiviral regimes. Protease inhibitors (PIs) stand as a prominent class of antiviral agents frequently utilized in AIDS management and have been significantly linked to premature senescence. This study aimed to investigate whether PI-containing regimens would accelerate osteoarthritis (OA) development and explore the molecular mechanisms underlying this association. A retrospective cohort of 151 HIV-infected individuals, categorized into PI and non-PI groups, was established. Patients in PI group exhibited lower KOOS and a higher prevalence of radiological knee OA than those in non-PI group. Additionally, 25 anti-HIV drugs were screened and among all antiviral drugs, lopinavir had the most detrimental impact on cartilage anabolism, accelerating cartilage senescence and promoting mouse OA development. Mechanistically, lopinavir accelerated cellular senescence by inhibiting Zmpste24 and interfering nuclear membrane stability, which leads to decreased binding between nuclear membrane-binding protein Usp7 and Mdm2 and activates Usp7/Mdm2/p53 pathway. Zmpste24 overexpression reduces OA severity in mice. These findings suggest that PI-containing regimens accelerate cartilage senescence and OA development through Zmpste24 inhibition, which provides new insights into the selection of HIV regimens.

Caloric restriction and methionine restriction-driven enhanced lifespan and healthspan induces 'browning' of white adipose tissue, a metabolic response that increases heat production to defend core body temperature. However, how specific dietary amino acids control adipose thermogenesis is unknown. Here, we identified that weight loss induced by caloric restriction in humans reduces thiol-containing sulfur amino acid cysteine in white adipose tissue. Systemic cysteine depletion in mice causes lethal weight loss with increased fat utilization and browning of adipocytes that is rescued upon restoration of cysteine in diet. Mechanistically, cysteine-restriction-induced adipose browning and weight loss requires sympathetic nervous system-derived noradrenaline signalling via β3-adrenergic-receptors that is independent of FGF21 and UCP1. In obese mice, cysteine deprivation induced rapid adipose browning, increased energy expenditure leading to 30% weight loss and reversed metabolic inflammation. These findings establish that cysteine is essential for organismal metabolism as removal of cysteine in the host triggers adipose browning and rapid weight loss.

Age-related hearing loss (ARHL) is one of the most common health conditions among the elderly population. This study used machine learning to screen for a gene signature to predicts ARHL. Four ARHL mice cochlear transcriptome datasets and the mRNA sequencing of C57BL/6J mice were used for analysis. Machine learning was used to screen for gene signatures closely related to ARHL and validate them. Via qPCR, immunohistochemistry, and immunofluorescence confocal microscopy were used to assess the effect of key gene on the cochlea. The gene signature consisting of 38 genes constructed via Stepglm [forwards] had the best accuracy in the training group, with excellent accuracy and recall in the training and testing groups in predicting ARHL. The gene signature reflected active immune function. CTSS was selected as a key gene on the basis of its association with age and influence hearing loss severity. CTSS showed high expression in ARHL and enriched in the cochlear stria vascularis, which is significantly positively correlated with macrophage marker CD68 expression (R = 0.74, p = 0.006). The gene signature has good accuracy in predicting ARHL. CTSS is highly expressed in the cochleae of ARHL mice and may promote ARHL by inducing macrophage enrichment and causing low-grade inflammation.

Platelet-derived materials are emerging as promising, cell-free biotherapies for regenerative medicine. While platelet lysates have shown neuroprotective activity in preclinical models, the neurogenic potential of platelet concentrate-derived extracellular vesicles (pEVs) remains underexplored. Here, we evaluated the effects of human pEVs and a neuroprotective heat-treated human platelet lysate (HPPL) on adult hippocampal neurogenesis using both an ex vivo neurosphere assay and an in vivo intranasal administration model. pEVs selectively enhanced dentate gyrus (DG)-derived neurosphere growth, even in the absence of exogenous growth factors, and were internalized by neural precursors. In vivo, short-term pEV delivery increased EdU proliferating cells in the DG, while long-term administration (28 days) elevated the proportion of newborn mature neurons. By contrast, HPPL primarily promoted early neurogenesis by expanding immature DCX neurons. Quantitative proteomics of DG tissue after pEV treatment revealed 111 differentially expressed proteins, with enrichment in pathways related to oxidative phosphorylation, Notch4 signaling, myelination, and MHC class I-mediated antigen presentation. Downregulated proteins included cytoskeletal and translation-related regulators, suggesting a shift toward neuronal differentiation and circuit integration. Biophysical characterization confirmed the purity and vesicular nature of pEVs, with a defined protein cargo including immune modulators and ECM-interacting molecules such as CD44, lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), and complement proteins. These findings identify allogeneic pEVs as multifunctional agents that modulate neural precursor cell fate and brain tissue remodeling through coordinated metabolic and immunoregulatory mechanisms. This work supports the translational potential of pEV-based therapeutics for promoting hippocampal neurogenesis and cognitive repair in neurodegenerative and age-related brain disorders.

Reactive thiols of proteinaceous cysteines are vital to cell biology by serving as sensor, effector and buffer of environmental redox fluctuations. Being the major source, as well as the prime target, of reactive oxygen species (ROS), mitochondria confront great challenges in preserving their thiol pool. Here we show that ROS modulator 1 (ROMO1), a small inner mitochondrial membrane protein, plays a role in protecting the mitochondrial cysteinome. ROMO1 is redox sensitive and reactive and overexpression can prevent deleterious oxidation of proteinaceous thiols. ROMO1 upregulation leads to a reductive shift of the mitochondrial cysteinome, exerting beneficial effects on mitochondria, such as promoting energy metabolism and Ca

Biological Age Acceleration (BAA), as quantified by epigenetic clocks, is a well-established biomarker for mortality and age-related morbidity. This study aimed to investigate the independent and combined associations of sleep duration, sedentary behavior, and physical activity with BAA risk.

Measurements of mitochondrial morphology are a powerful proxy for assessing mitochondrial health, particularly during aging when organelle dynamics are disrupted.

This study aimed to investigate the potential causal relationship between 731 immune cell traits and age at natural menopause (ANM), a measurable endpoint for ovarian aging.

Ferroptosis plays a role in wound healing during the maturation of senescent endothelial cells. This study explores the modulation of ferroptosis in senescent human umbilical vein endothelial cells (HUVECs) and wound-healing processes by Piezo1 activation at the molecular, cellular, and tissue levels. Elevated Piezo1 expression was observed in HUVECs treated with the senescence inducer doxorubicin (Doxo) and the ferroptosis inducer erastin and in aged wound tissue. Pharmacological inhibition or knockdown of Piezo1 protected senescent HUVECs and aged wound tissue from ferroptosis. Additionally, Piezo1 channel activity was found to promote ferroptosis in senescent HUVECs by increasing intracellular Ca

Hematopoietic stem cell (HSC) transplantation offers a cure for a variety of blood disorders, predominantly affecting the elderly; however, its application, especially in this demographic, is limited by treatment toxicity. In response, we employ a murine transplantation model based on low-intensity conditioning protocols using antibody-mediated HSC depletion. While aging presents a significant barrier to effective HSC engraftment, optimizing HSC doses and non-genotoxic targeting methods greatly enhance the long-term multilineage activity of the transplanted cells. We demonstrate that young HSCs, once effectively engrafted in aged hosts, improve hematopoietic output and ameliorate age-compromised lymphopoiesis. This culminated in a strategy that robustly mitigates disease progression in a genetic model of myelodysplastic syndrome. These results suggest that non-genotoxic HSC transplantation could fundamentally change the clinical management of age-associated hematological disorders, offering a prophylactic tool to delay or even prevent their onset in elderly patients.

During fetal development, lifelong hematopoietic stem cells (HSCs) emerge from hemogenic endothelium as a part of the intra-arterial hematopoietic clusters. These definitive HSCs are deemed to colonize and expand in the fetal liver, migrate to the bone marrow, and produce mature blood cells throughout life. However, emerging lines of evidence have challenged this paradigm, and alternative models have been proposed. Moreover, recent studies have revealed expansion of HSCs during aging, which seems counterintuitive to their age-dependent reduction in regenerative capacity. Here, we summarize emerging views on hematopoietic ontogeny and aging, which was the focus of the Summer 2024 International Society for Experimental Hematology (ISEH) webinar.

Biological aging and pressure overload-induced left ventricular cardiac hypertrophy (PO-CH) is marked by myocardial thickening, fibrosis, and functional decline, heightening the risk of heart failure. To advance therapeutic monitoring and intervention, we aimed to identify drug-responsive biomarkers with functional relevance to disease progression. Using rat models of biological aging (BA) and PO-CH, we evaluated the cardioprotective effects of Amalaki Rasayana (AR), a traditional nutraceutical, and its bioactive constituent gallic acid (GA), while concurrently profiling candidate serum biomarkers. Galectin-3 was present in full-length and oligomeric forms, with C-terminal (C-epitope) homo-oligomers closely associated with pathological remodeling. AR and GA significantly reduced these oligomers via cytoplasmic retention and phosphorylation-dependent downregulation of galectin-3 secretion, mitigating maladaptive cardiomyocyte signaling. Levels of atrial natriuretic peptide (ANP), cyclophilin A (PPIA), and albumin (ALB) showed consistent changes, reinforcing their utility as therapeutic response indicators. Findings were validated in sera from aged humans and patients responsive to clinical treatment, confirming translational potential. This study establishes a novel biomarker panel-galectin-3 C-epitope, ANP, PPIA, and ALB-for monitoring treatment efficacy and positions AR as a promising intervention in cardiac hypertrophy.

Information on individual age is a fundamental aspect in many ecological and evolutionary studies. However, accurate and non-lethal methods that can be applied to estimate the age of wild animals are often absent. Furthermore, since the process of ageing is accompanied by a physical decline and the deterioration of biological functions, the biological age often deviates from the chronological age. Epigenetic marks are widely suggested to be associated with this age-related physical decline, and especially changes in DNA methylation are suggested to be reliable age-predictive biomarkers. Here, we developed separate epigenetic clocks for ageing and development in a small passerine bird, the great tit (Parus major). The ageing clock was constructed and evaluated using erythrocyte DNA methylation data of 122 post-fledging individuals, and the developmental clock using 67 pre-fledging individuals from a wild population. Using a leave-one-out cross-validation approach, we were able to accurately predict the ages of individuals with median absolute deviations of 0.40 years for the ageing and 1.06 days for the development clock. Moreover, using existing data from a brood-size manipulation, we show that nestlings from reduced broods are estimated to be biologically older compared to control nestlings, while they are expected to have higher fitness. These epigenetic clocks provide further evidence that, as observed in mammals, changes in DNA methylation of certain CpG sites are highly correlated with chronological age in birds and this opens up new avenues for broad applications in behavioural and evolutionary ecology.

Macronutrients profoundly affect both lifespan and reproduction and also modulate the fundamental trade-off between these two components of fitness in many insects. Beetles represent the largest group of insects, but nutritional interventions in lifespan and reproduction have never been thoroughly explored in this taxon. Here, we used nutritional landscape methodology to determine the effects of protein and carbohydrate intake on lifespan and reproduction in the mealworm beetle, Tenebrio molitor (Coleoptera: Tenebrionidae). The time of death and last reproduction, the number of eggs laid, and protein-carbohydrate intake were recorded from beetles maintained on one of 35 chemically defined foods varying in protein-to-carbohydrate ratio (P:C=0:1, 1:5, 1:2, 1:1, 2:1, 5:1, or 1:0) and in protein plus carbohydrate concentration (P+C=25.2, 33.6, 42, 50.4, or 58.8 %). Lifespan and reproductive traits increased with higher caloric intake, but their respective trait maxima occurred at different P:C ratios. Female reproductive traits peaked at higher P:C ratios (reproductive lifespan: 1:1.06; lifetime egg production: 1.31:1; egg production rate: 1.75:1) than those maximizing lifespan (male lifespan: 1:1.38; female lifespan: 1:1.36). This divergence indicates a nutrient-mediated trade-off between lifespan and reproduction in this species. Despite this, this nutritional conflict in T. molitor appeared to be less pronounced than what has been observed in other species commonly used in insect ageing research. When given a food choice, T. molitor beetles selected a P:C ratio close to 1:1, which simultaneously supported extended lifespan and high reproductive output.

Werner syndrome (WS) is a rare hereditary progeroid syndrome caused by mutations in the WRN gene. Patients frequently develop various age-associated diseases prematurely, often leading to early mortality (≤ 60 years of age). Depletion of nicotinamide adenine dinucleotide (NAD)

Mesenchymal stem cells (MSCs) have potential for treating degenerative and immune diseases, but their clinical efficacy is limited by senescence, characterized by mitochondrial dysfunction, impaired mitophagy, and metabolic imbalance. The goal of this study was to investigate the effects of dimethyloxalylglycine (DMOG), a hypoxia-mimetic agent that stabilizes hypoxia-inducible factor 1 alpha (HIF-1α), on rejuvenating senescent MSCs by enhancing mitochondrial function, mitophagy, and metabolic reprogramming.

Tobacco smoke is the main cause of preventable mortality worldwide. Smoking increases the risk of developing many diseases and has been proposed as an aging accelerator. Yet, the molecular mechanisms driving smoking-related health decline and aging acceleration in most tissues remain unexplored.

Cardiac aging is sexually dimorphic, with women more likely than men to develop diastolic dysfunction for which no therapies exist. Loss of estrogen (E2) during menopause increases risk of diastolic dysfunction in women through unclear mechanisms. Citrullination, a post-translational modification catalyzed by peptidylarginine deiminase 2 (PAD2) is positively regulated by E2, suggesting a novel mechanism linking PAD2, diastolic function, and E2 in the female heart. We hypothesized that PAD2 expression and citrullination are sexually dimorphic with aging such that as E2 levels decline, so does PAD2 expression and citrullination, contributing to diastolic dysfunction. PAD2 expression decreased with age in female mice but not in the aging male heart. Mass spectrometry detected citrullination of sarcomeric and metabolic proteins, with lower levels of citrullinated proteins in aged female hearts compared to young. To confirm direct regulation of PAD2 by E2, a cohort of young (2 month) and aged (21 month) mice underwent ovariectomy (OVX) with or without E2 replacement. Contrary to our hypothesis, PAD2 expression was not regulated by E2 in the heart. To directly link PAD2 and diastolic function, we assessed cardiac function in middle-aged female global PAD2 knockout mice and found that loss of PAD2 resulted in diastolic dysfunction. Together, we establish that protein citrullination and PAD2 decline with age in the female heart, perhaps contributing to diastolic dysfunction. Elucidation of the mechanisms underlying PAD2 declines in the female heart remains to be determined and may benefit development of therapies for diastolic dysfunction for aging women.

This study examines the association between the timing of menopause and hysterectomy and biological aging, focusing on epigenetic and physiological aging markers.

Age-related physiological changes in older adults involve a rapid decline in motor exercise ability; some older adults may also experience difficulties in maintaining focus, memory loss, and a decline in reaction time, which consequently impair their ability to perform dual tasks. Motor-cognitive training (MCT) refers to a blend of motor activity and cognitive training that occurs simultaneously and can assist older adults in enhancing their physical function, cognitive abilities, and dual-task performance. In recent years, the use of technology for delivering MCT has become increasingly popular in research. This has been achieved through various technologies that simplify MCT for older adults.

A major aging hallmark is the accumulation of cellular senescence burden. Over time, senescent cells contribute to tissue deterioration through chronic inflammation and fibrosis driven by the senescence-associated secretory phenotype (SASP). The human ovary is one of the first organs to age, and prominent age-related fibroinflammation within the ovarian microenvironment is consistent with the presence of senescent cells, but these cells have not been characterized in the human ovary. We thus established a doxorubicin-induced model of cellular senescence to establish a "senotype" (gene/protein signature of a senescence cell state) for ovarian senescent cells. Explants of human postmenopausal ovarian cortex and medulla were treated with doxorubicin for 24 h, followed by culture for up to 10 days in a doxorubicin-free medium. Tissue viability was confirmed by histology, lack of apoptosis, and continued glucose consumption by explants. Single nuclei sequencing and proteomics revealed an unbiased signature of ovarian senescence. We identified distinct senescence profiles for the cortex and medulla, driven predominantly by epithelial and stromal cells. Proteomics uncovered subregional differences in addition to 120 proteins common to the cortex and medulla SASP. Integration of transcriptomic and proteomic analyses revealed 26 shared markers, defining a senotype of doxorubicin-induced senescence unique to the postmenopausal ovary. A subset of these proteins: Lumican, SOD2, MYH9, and Periostin were mapped onto native tissue to reveal compartment-specific localization. This senotype will help determine the role of cellular senescence in ovarian aging, inform biomarker development to identify, and therapeutic applications to slow or reverse ovarian aging, senescence, and cancer.

Cellular epigenetic aging has become an important marker of healthy or unhealthy aging. The current study examined whether lifelong cumulative stressors across multiple domains were linked with epigenetic age acceleration (EAA; i.e., epigenetic age greater than chronological age) and whether psychological factors moderated this association. Dimensions of psychological well-being were hypothesized as protective factors, while neuroticism was posited as a vulnerability factor.

This study investigates the effects of N‑PEP‑12, a neuroprotective dietary supplement, on cognitive function, neuroplasticity, and neurogenesis in aged 129S1/SvImJ (S1) mice, which are known for age‑associated cognitive impairments. The primary objective was to determine whether N‑PEP‑12 could improve memory retention and enhance neural health by modulating hippocampal plasticity and neurogenesis. S1 mice were chronically treated with N‑PEP‑12 or a Vehicle to assess its impact on cognitive performance using cued fear conditioning (CFC) and object location memory (OLM) tests. Additionally, in vitro studies examined the effects of N‑PEP‑12 on neuroplasticity markers such as Neurofilament Light Chain (NF‑L) expression and vasopressin (AVP) promoter methylation, to elucidate the molecular mechanisms underlying cognitive enhancements. N‑PEP‑12 treatment significantly improved associative and contextual memory in the CFC and OLM tests respectively. In vitro assays revealed that N‑PEP‑12 increased NF‑L expression and decreased AVP promoter methylation, indicating enhanced neuroplasticity and neurogenesis. Furthermore, N‑PEP‑12 preserved blood‑brain barrier integrity under oxidative stress conditions, suggesting a protective role against vascular‑related cognitive decline. The findings suggest that N‑PEP‑12 promotes hippocampal health by enhancing neurogenesis and neuroplasticity, potentially mitigating age‑related cognitive decline. These results highlight N‑PEP‑12 as a promising agent for supporting healthy cognitive function in aging populations through the modulation of neurobiological pathways associated with learning and memory.

Telomeres are repetitive sequences of nucleotides at the end of chromosomes, whose evolution over time is intrinsically related to biological ageing. In most cells, with each cell division, telomeres shorten due to the so-called end replication problem, which can lead to replicative senescence and a variety of age-related diseases. On the other hand, in certain cells, the presence of the enzyme telomerase can lead to the lengthening of telomeres, which may delay or prevent the onset of such diseases but can also increase the risk of cancer. In this article, we propose a stochastic representation of this biological model, which takes into account multiple chromosomes per cell, the effect of telomerase, different cell types and the dependence of the distribution of telomere length on the dynamics of the process. We study theoretical properties of this model, including its long-term behaviour. In addition, we investigate numerically the impact of the model parameters on biologically relevant quantities, such as the Hayflick limit and the Malthusian parameter of the population of cells.

Protein carbamylation is a non-enzymatic post-translational modification, potentially increasing the risk of misfolding diseases. However, studies on carbamylation in recent years have focused only on amyloid aggregation, ignoring its effect on more toxic oligomers. Additionally, the behavior of proteins in dilute solutions does not fully reflect how these molecules function in their physiological environment. To address these concerns, this study developed a protein carbamylation system using potassium cyanate and used dextran 70 (300 g/L) as a crowding agent to clarify the effects of macromolecular crowding on carbamylated protein homeostasis, especially its effect on oligomers with membrane-damaging capacity, thereby elucidating the role of carbamylation in the onset and progression of protein misfolding diseases and achieving extracellular biomimetic mimicry of intracellular protein behavior. The results indicate that potassium cyanate can form hydrogen bonds and van der Waals interactions with proteins, undergoing nucleophilic addition reactions, which increases the free radical content in the system and induces protein misfolding, oxidative damage, amyloid aggregation and oligomerization. Moreover, under the macromolecular crowding environment, protein carbamylation and its induced misfolding and oxidative aggregation are aggravated accompanied by a reduction in amyloid aggregation and an increase in oligomer formation. These findings provide insights into the molecular and biochemical basis of protein misfolding diseases triggered by carbamylation and may offer potential biomarkers for the early diagnosis and treatment of such diseases, further achieving high-throughput screening of drugs for the prevention and treatment of age-related diseases.

Leukocyte recruitment to sites of inflammation is vital for orchestrating an effective immune response. Key to this process is the ability of leukocytes to migrate through venular walls, engaging in sequential interactions with endothelial cells, pericytes, and the venular basement membrane. The aging process exerts profound effects on the molecular and functional properties of the vasculature, thereby influencing the profile and dynamics of leukocyte trafficking during inflammation. In this review, by focusing mainly on neutrophils, we summarize key examples of how the aged microvasculature and perivascular stroma cells promote dysregulated leukocyte-venular wall interactions and present the associated molecular mechanisms. Additionally, we discuss the functional implications of such aberrant leukocyte behavior to age-related and chronic inflammatory pathologies.

Alterations to the extracellular matrix of skeletal muscle are implicated in age-related declines in muscle quality. Reduced collagen breakdown and collagen accumulation between muscle fibres are suggested to reduce the force-generating capacity of the muscle and impede adaptation to mechanical loading. The current study investigated total intramuscular collagen content in healthy, physical fitness-matched young and older skeletal muscle and how regulators of collagen breakdown respond to an acute bout of resistance exercise. No differences in intramuscular collagen content between young (5.4% ± 2.1) and older muscle (5.1% ± 3.1, p=0.779) were found. Seventy-two hours after resistance exercise, matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinase (TIMP) gene expression (

Learning and memory impairment is one of the main manifestations of cognitive impairment. Gut flora can affect cognitive function and behavior through the gut-brain axis. Ganoderma lucidum polysaccharide (GLP) is one of the main effective components of G. lucidum, with antioxidant and anti-aging effects. In this study, the learning and memory impairment model of aging mice was established by injecting D-galactose (D-gal). The learning and memory ability of mice was tested by a water maze experiment. Also, the biochemical indexes of mouse serum and brain tissue were determined. In addition, 16S rRNA sequencing was performed on mouse feces. The results showed that GLP significantly shortened the latency of mice to find a safe platform. Also, they enhanced superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, increased glutamate (Glu) and acetylcholine (ACh) contents, and decreased malondialdehyde (MDA) and gamma-aminobutyric acid (GABA) contents in mice to improve antioxidant capacity, remove free radicals, and reduce lipid peroxidation and oxidative stress, thereby improving learning and memory disorders in mice. The analysis of the microflora after the intervention of GLP to improve learning and memory disorders in mice revealed changes in Lactobacillus abundance. In conclusion, D-gal causes learning memory impairment and reduced intestinal microbial diversity in aging mice, whereas GLP may ameliorate learning memory impairment by altering the distribution of Lactobacillus in the intestinal tract of mice and regulating the biosynthesis of peptidoglycan and secondary bile acids.

Discrimination is a prominent stressor among older adults tied to a greater risk of disability, morbidity, and mortality. However, the underlying biological mechanisms by which discrimination impacts health outcomes are not clear. We investigated the relationship between discrimination and accelerated biological aging. We also evaluated the sensitivity of that association to the inclusion of potential health risk pathways, which link discrimination to accelerated biological aging.

We previously demonstrated that neurotensin, a 13-amino-acid gut hormone peptide, enhances small intestinal epithelial cell fatty acid uptake through inhibition of AMPK. Here, utilizing Drosophila and mouse models in vivo, as well as mouse and human small intestinal epithelial organoids or monolayers ex vivo, we determine the targets of neurotensin and AMPK associated with obesity and aging. High-fat diet and aging decreased AMPK and insulin signaling, which was prevented by neurotensin deficiency. High-fat diet feeding increased FABP1 protein expression in wild-type mice; this effect was attenuated in neurotensin-deficient mice. AICAR and metformin increased AMPK phosphorylation in young but not in aged small intestinal epithelial cells. By contrast, AICAR and metformin inhibited FABP1 mRNA and protein expression. Moreover, cytosolic colocalization of AMPKα1 and FABP1 was noted in IEC-6 cells. AMPK phosphorylation and FABP1 expression was decreased in aged wild-type small intestinal epithelial cells; however, this effect was reversed in neurotensin-deficient cells. Results from human duodenal organoids confirm the effects of neurotensin, palmitic acid and metformin on AMPK phosphorylation and FABP1. Finally, overexpressing neurotensin in enteroendocrine cells reduced the lifespan of Drosophila; neurotensin deficiency extended the lifespan of mice fed a high-fat diet. Our findings indicate that neurotensin inhibits AMPK and increases FABP1 in small intestinal epithelial cells under conditions of obesity. Neurotensin deficiency preserves AMPK and FABP1 levels, thus attenuating some of the negative effects of obesity and aging.

Background. The association between plants and soil microbes is critical for both soil and plant health. Studies have shown that introducing beneficial microbial inoculants can shape the soil microbiome community for plant health. Among these microbes, mycorrhizal fungi play a well-documented role in enhancing nutrient uptake in plants. Ergothioneine (ERGO), a compound well-known for its anti-inflammatory and antioxidant properties, has been linked to increased longevity in various model systems and its significance for human health. However, neither animals nor plants contain ERGO biosynthetic pathways, which are limited to fungi, including and some species of bacteria, including Actinomyceota, Cyanobacteria, and Methylobacteria. Though the leading dietary sources of ERGO for humans are fungi in the form of mushrooms or fermented foods, biofortification of crops by promoting the production and uptake of ERGO from microbial sources in the soil has promise for enhancing nutritional quality and public health outcomes. Results. This study explores the of interaction between soil ERGO application and arbuscular mycorrhizal fungi (AMF) in plant-symbiotic relationships to increase the ERGO content in the staple crop wheat (Triticum aestivum). We investigate how ERGO supplementation, both alone and in combination with AMF, influences the wheat root and soil microbiome in a greenhouse experiments. Our data shows that plants can take up ERGO in absence of AMF fungi. In addition, treatment with pure ERGO and ERGO in combination with AMF altered microbial diversity and community structure in both the rhizosphere and rhizoplane regions of wheat roots. Conclusions. Overall, our work reveals that plants can readily take up ERGO from soil, both with and without AMF presence, highlighting a broader role of ERGO in connecting soil health to human health, a connection that warrants further investigation.